Method for terminating cancer cells with an azole-based compound

Abstract

A combination therapy involving different therapeutic molecules can enhance and improve the therapeutic potentials. An effective therapeutic strategy conjugates silica (SiO2) nanoparticles with, e.g., 3-glycidyloxypropyl, trimethoxysilane and azoles, e.g., 1,2,4-triazole (Tri), 3-aminotriazole (ATri), 5-aminetetrazole (Atet), imidazole (Imi). These exemplary materials—classified as SiO2-3GPS-Tri (Conj. 1), SiO2-3GPS-Atri (Conj. 2), SiO2-3GPS-Atet (Conj. 3), SiO2-3GPS-Btri (Conj. 4), and SiO2-3GPS-Imi (Conj. 5)—can amplify targeting of therepeutics for human colorectal carcinoma cells (HCT-116), enhancing anti-cancer effects.

The invention claimed is: 
     
       1. A method of bringing about human colorectal cancer cell death, the method comprising:
 exposing cancer cells to a 1 to 10 mg/mL solution of a conjugate compound for a period of no more than 96 hours, thereby reducing a cancer cell survival rate to no more than 50% the amount of a control. 
 wherein the conjugate compound comprises, in reacted form:
 a silicon dioxide nanoparticle having a surface modified with a linker of Formula (1)
   (C 1-5 O—) 3 -Si-C 2-10 -O-C 1-10 -oxirane   (1a),
 
 
 
 and an azole, 
 wherein the nanoparticle comprises at least 85 wt. % silica, based on total nanoparticle weight, 
 wherein, in the reacted form, the silicon of the linker forms a covalent bond to at least one of the oxygen atoms of the silicon dioxide of the nanoparticle, 
 wherein the azole, in the reacted form, is covalently bonded with a carbon atom of the oxirane via ring-opening of the oxirane of the linker with the azole, as an optionally substituted hydroxymethine-methylene-azole unit, and 
 wherein the azole of the conjugate compound is 1,2,4-triazole, 3-amino-1,2,4-triazole, 5-aminotetrazole, 1H-benzotriazole, or imidazole. 
 
     
     
       2. The method of  claim 1 , wherein the silicon dioxide nanoparticle of the conjugate compound is non-magnetic. 
     
     
       3. The method of  claim 1 , wherein the silicon dioxide nanoparticle of the conjugate compound comprises at least 97.5 wt. % silica, relative to the total nanoparticle weight. 
     
     
       4. The method of  claim 1 , wherein the cancer cells comprise HCT-116 cells. 
     
     
       5. The method of  claim 1 , wherein the linker of Formula (1) of the conjugate compound has Formula (1a):
   (C 1-30 O—) 3 -Si-C 2-5 -O-C 1-3 -oxirane   (1a).
 
 
     
     
       6. The method of  claim 1 , wherein the linker of the conjugate compound comprises, in reacted form, (3-glycidyloxypropyl)-trimethoxysilane and/or (3-glycidyloxypropyl)-triethoxysilane. 
     
     
       7. The method of  claim 1 , wherein the silicon dioxide nanoparticle of the conjugate compound has a bulk density in a range of from 0.008 to 0.015 g/mL. 
     
     
       8. The method of  claim 1 , wherein the conjugate compound enhances cell death of cancer cells exposed to the conjugate compound, at least 50% more relative to cell death of cancer cells exposed to a placebo within 48 hours of exposure. 
     
     
       9. The method of  claim 1 , wherein the cell death arises from nuclear condensation, nuclear augmentation, and/or cell membrane disruption. 
     
     
       10. A method of treating a colorectal cancer, comprising:
 administering to a patient in need thereof an effective amount of a conjugate compound, 
 wherein the conjugate compound comprises, in reacted form:
 a silicon dioxide nanoparticle having a surface modified with a linker of Formula (1):
   (C 1-5 O—) 3 -Si-C 2-10 -O-C 1-10 -oxirane   (1)
 
 
 
 and an azole, 
 wherein the nanoparticle comprises at least 85 wt. % silica, based on total nanoparticle weight, 
 wherein, in the reacted form, the silicon of the linker forms a covalent bond to at least one of the oxygen atoms of the silicon dioxide of the nanoparticle, 
 wherein the azole, in the reacted form, is covalently bonded with a carbon atom of the oxirane, via ring-opening of the oxirane of the linker with the azole, as an optionally substituted hydroxymethine-methylene-azole unit, and wherein the azole of the conjugate compound is 1,2,4-triazole, 3-amino-1,2,4-triazole, 5-aminotetrazole, 1H-benzotriazole, or imidazole. 
 
     
     
       11. A method of bringing about cancer cell death of human colorectal cancer cells, the method comprising:
 contacting the human colorectal cancer cells with a conjugate compound; 
 wherein the conjugate compound comprises, in reacted form:
 a silicon dioxide nanoparticle having a surface modified with a linker of Formula (1):
   (C 1-5 O—) 3 -Si-C 2-10 -O-C 1-10 -oxirane   (1),
 
 
 
 and an azole, 
 wherein the nanoparticle comprises at least 85 wt. % silica, based on total nanoparticle weight, 
 wherein, in the reacted form, the silicon of the linker forms a covalent bond to at least one of the oxygen atoms of the silicon dioxide of the nanoparticle, 
 wherein the azole, in the reacted form, is covalently bonded with a carbon atom of the oxirane of the linker, via ring-opening of the oxirane with the azole, as an optionally substituted hydroxymethine-methylene-azole unit, and 
 wherein the azole is 1,2,4-triazole, 3-amino-1,2,4-triazole, 5-aminotetrazole, 1H -benzotriazole, or imidazole.